Derivatives of the di-hydroxy-benzenes and process for manufacture of same



Patented May 22, 1934 DERIVATIVES THE DI-HYDROXY-BEN- ZENES AND PROCESSFOR MANUFACTURE OF S Marcus Guggenheim, to Hoffmann-La Basel,Switzerland, assignor Roche Inc., Nutley, N. J., a

corporation of New Jersey No Drawing. Application May 5, 1933, SerialNo.

10 Claims.

The mono-ethers of the'di-hydroxy-benzenes of the general formulaC6H4(OH)OR, R being an aryl, aralkyl or an alkyl with more than 4 carbonatoms, are known as very strong disinfectants 5 (Klarmann, Journal ofthe American Chemical Society, vol. 54, 1932, p. 1206). They are howevernot Well suited for internal use, because they are scarcely soluble inWater, have an exceedingly disagreeable taste and irritate the mucousmembranes of the mouth.

It has now been found, that the salts of the acid phosphoric acidvesters of these di-hydroXy-benzene-mono-ethers have only a very slighttaste and no irritating efiect. They are slowly saponil5 fied in. theorganism. The salts of the acid phosphoric acid esters are obtained byboiling the mono-ethers of the di-hydroXy-benzenes withphosphorous-oxyhalogenides. saponifyin'g the halogenides of the acidphosphoric acid esters of the di-hydroXy-benzene-mono-ethers andconverting the free acid phosphoric acid esters of thedi-hydroxy-benzene'-mono-ethers by neutralization into their salts. Forobtaining the halogemdes of the acid phosphoric acid esters of thed'i-hydroxy-benzene-mono ethers it may be advantageous to use catalysts,such as phosphorouspentachloride or quinoline, but the reaction alsosets in without these catalysts, if the heating is continued longenough. According to the proportionsof the starting material and thephosphorusoxyhalogenide used the halogenides of the monoesters or of thedi-esters are obtained. With a large. excessof phosphorus-oxyhalogenidepractically only the halogenides of the mono-esters are obtained. Bysaponifying the acid chlorides with warm water only, the correspondingmonoether-acids are obtained from the halogenides of the mono-esters. Bysaponifying with alkali ester-acids of the type of pyrophosphoric acidare 40 obtained. Of all these substances the salts of themono-ester-acids are the most suitable owing to their readycrystallization and the ease with which the intermediate compounds canbe isolated. The reactionstaking place in their preparation by the abovemethod canbe represented by the following equations:

In these equationsR represents asubstituted or unsubstituted aryl,aralkyl or an alkyl with more than 408;].13011 atoms, X a halogen.

In Germany May 14, 1932 The new compounds are to be used as internaldisinfectants.

Example 1 20' parts by weight of hydroquinone-mono- 6 phenylether areboiled with 200 parts by weightof pure distilled phosphorus-oxychloridefor 100" hours with a reflux condenser. After removing the excess ofphosphorus oxychloride, distillation is continued in vacuo and 28 partsby weight of mono -p-phenoxy-pheny lphosphoric ester-aciddichloride,boiling at 206- 209 C. under 11 mm. pressure, are obtained. The compoundmelts at 53 C. The same compound maybe obtained with the same yield, if20 parts by weight of hydro Illquinone-monophenylether are boiled with200 parts by weight of phosphorus-oxychloride and 1 part by weight ofphosphorus-p'entachlori'de for 3 1 hours with a reflux condenser, andthe chloride thus obtained is purified by distillation- 1O parts byweight of the acid chloride thus obtained are stirred with 40 parts byweight of water for 3 hours at C. After cooling themono-p-phenoxyphenyl-phosphoric-ester-acid is isolated by shaking withether. After removing the ether by evaporation a'slowly congealing oilremains, which crystallizes from chloroform in leaflets melting at127-129 C.

In order to obtain the di-sodium salt of the" mono-p phenoxyp'henylphosphoric ester acid the acid is dissolved in alcohol andsodium-ethylate in alcoholic solution is added until the reactionbecomes neutral. The di-sodium salt is immediately precipitated in'crystalline form. It is easily soluble in water. With calcium-chloridethe aqueous solution yields a precipitate of the diffic'ultly solublecalcium salt of the acid.

' The hexamethylentetramine salt is obtained by dissolving equimolecularquantities of hexameth- I ylentetram-ine andmono-p-phenoxyphenyl-phosph'oric ester-acid in warm alcohol. On coolingthe salt crystallizes in the form of colorless needles.

Example 2 pr essure'. 1 l0 H 30 minutes at 90100 C. and after coolingthe 10 parts by weight of this acid chloride are stirred with 40 partsby weight of water for 5 hours at 85 C. After cooling themono-1-hydroxy-2-chloro-4-hydroxyphenyl phosphoric-ester-acid isisolated by shaking with ether and after evaporating the ether it isrecrystallized from carbon-tetra-chloride. It melts at 98- 100 C.

The sodium salt is obtained from an alcoholic solution in the form of acolorless powder in the manner described in Example 1.

Example 3 20 parts by weight of brenzcatechin-monophenylether are boiledwith 200 parts by weight of phosphorus-oxychloride, 1 part by weight ofphosphorus-pentachloride and 0.2 part by weight of quinoline for 3 /2hours with a reflux condenser. By distillation 25 parts by weight ofmono-ophenoxyphenyl-phosphoric ester acid -chloride boiling at 195198 C.under 11 mm. pressure are obtained.

10 parts by weight of this acid chloride are stirred with 40 parts byweight of water for 4 hours at 60 C. and themono-o-phenoxyphenylphosphoric-ester-acid is isolated by shaking withether and recrystallized from carbon-tetrachloa ride. It melts at121-123 C.

The ammonium salt is obtained by dissolving the acid in ether and addingammonia. The salt is immediately precipitated in crystalline form.

Example 4 20 parts by weight of hydroquinone-monobenzyl-ether, 200 partsby weight of phosphorus-oxychloride and 1 part by weight ofphosphorus-pentachloride are boiled for 3 /2 hours with a refluxcondenser. After evaporating the excess of phosphorus-oxychloride theremaining acid chloride is stirred with the 5-fold quantity of water formono p benzyl hydroxyphenyl phosphoric ester-acid is extracted byshaking with ether. The ether is then shaken with dilute soda-solutionand the acid is obtained in crystalline form by precipitating withdilute hydrochloric acid.

After recrystallization from a mixture of carbontetrachloride andchloroform it melts at 122- The ammonium salt is obtained in the mannerdescribed in Example 3.

Example 5 hydroxyphenyl-phosphoric ester-acid-dichloride melting at182184 C. under 11 mm. pressure are obtained by fractionation. Bysaponifying the acid chloride with warm water according to thedirections given in Example 1 themono-p-isoamyl-hydroxyphenyl-phosphoric-ester-acid is obtained whichcrystallizes from carbon-tetrachloride and melts at 5558 C. p

The ammonium salt is obtained in the manner described in Example 3.

Example 6 10 parts by weight of resorcinol-mono-phenylethyl-ether aredissolved with 15 parts by weight of phosphorus-oxychloride and 50 partsby weight of chloroform and 8 parts by weight of diethylaniline aredropped in at 5 to 0 C. After being left to stand for a night thesolvent and the excess of phosphorus-oxychloride are distilled off onthe water-bath at reduced pressure. The residue is taken up with ether,filtered from the diethylaniline-hydrochloride and the ether removed bydistillation. The dichloride is then saponified with water and thebicarbonatesoluble part isolated. Themono-(m-e-phenylethyl-hydroxy-phenyl-)phosphoric-ester-acid, a ratherthick oil, is taken up in absolute alcohol and the disodium salt isobtained in powdery white form by treatment with sodium-ethylate. Thesodium salt is easily soluble in water and reacts neutrally.

7 Instead of [diethylaniline phosphorus-pentachloride' may be used.

11 parts by weight of resorcinol-mono-phenylethyl-ether are heated with20 parts by weight of phosphorus-oXy-chloride with the addition of 0.1part of phosphorus-penta-chloride, until at 90-100 C. the development ofhydrochloric acid stops. The reaction product is then heated to boilingpoint and the excess of phosphorus-oxychloride removed by distillationin vacuo. The product is then treated in the same manner as previouslydescribed.

I claim:

1. The phosphoric-acid-ester-derivatives of dihydroxy-benzenes of theformula ROCeHeOPO (OH) 2,

R being a substituted or unsubstituted phenyl, phenalkyl, or a saturatedalkyl radical with more than four carbon atoms, forming wellcrystallized easily water soluble salts, and constituting good internaldisinfectants.

2. The mono-p-phenoxyphenyl-phosphoric-ester-acid crystallizing fromchloroform in leaflets melting at 127-129 0., forming a wellcrystallizing, easily water-soluble di-sodium salt and being a goodinternal disinfectant.

3. The process for the manufacture of esterderivatives ofdi-hydroxy-benzenes, which consists in heatingdi-hydroxy-benzene-mono-ethers of the general formula Cal-14(OH) OR, Rbeing a substituted or unsubstituted phenyl, phenalkyl, or saturatedalkyl radical with more than 4 carbon atoms, withphosphorus-oxyhalogenides and saponifying the acid halogenides.

4. The process for the manufacture of esterderivatives ofdi-hydroxybenzenes, which consists in heatingdi-hydroxy-benzene-mono-ethers of the general formula CsI-I4(OH) OR, Rbeing a substituted or unsubstituted phenyl, phenalkyl, or saturatedalkyl radical with more than 4 carbon atoms, withphosphorus-oxyhalogenides in the presence of a catalyst selected fromthe group which consists of phosphorous pentachloride, quinoline, anddiethylaniline, and saponifying the acid halogenides.

5. The process for the manufacture of esterderivatives ofdi-hydroxy-benzenes, which consists in heatingdi-hydroxy-benzene-mono-ethers of the general formula CsI-I4(OH) OR, Rbeing a substituted or unsubstituted phenyl, phenalkyl, or saturatedalkyl radical with more than 4 carbon atoms, withphosphorus-oxychlorides and saponifying the acid chlorides. v

6. The process for the manufacture of esterderivatives ofdi-hydroxy-benzenes, which consists in heatingdi-hydroxy-benzene-mono-ethers of the general formula C6H4(OH) OR, Rbeing a substituted or unsubstituted phenyl, phenalkyl, or

ohm, and diethy'ianiline, and saponifying the acid haiogenides.

9. The process for the manufacture ofmono-pphenoxy-phenyl-phosphoric-ester-acid, which consists in heatinghydroquinone-mono-pheny1- ether with phosphorus-oxychloride andsaponiiying the acid chloride.

10. The process for the manufacture ofmono-pphenoxy-pheny1-phosphoric-ester-acid, which consists in heatinghydroquinone-mono-pheny1- ether with phosphorus-oxychloride in thepresence of a catalyst selected from the group which consists ofphosphorus pentachloride, quinoline, and diethyianiline, and saponifyingthe acid chloride.

MARCUS GUGGENHEIM.

